American Indians and Alaska Natives (AI/ANs) have the highest smoking rates of the major racial/ethnic groups in the United States, approaching 40% to 50%. In addition, this underserved population has very low smoking cessation and abstinence rates. The smoking-attributable mortality rate of AI/ANs is not only the highest but double that of other ethnic groups. To date, there have been almost no studies that have focused on methods to encourage smoking cessation among AI/AN smokers and no randomized clinical trials. There is a desperate need for effective, culturally tailored cessation programs. We propose a 2 arm, and group randomized clinical trial to be conducted at 2 sites in the Midwest (Kansas and Oklahoma). We have begun to address these issues through the creation of the All Nations Breath of Life (ANBL) smoking cessation program using community-based participatory research methods. ANBL is group-based and is culturally-sensitive in all program components. It recognizes the sacred role of tobacco among many AI/ANs and how culture affects smoking cessation among AI/AN, while still addressing recreational smoking. Our pilot work shows promise for reducing cigarette smoking in AI/AN smokers, with quit rates of 30% at six months post-baseline, compared to 8-10% quit rates in other published studies. All participants in the proposed study will be offered pharmacotherapy (e.g. Varenicline or Bupropion or NRT) then randomized into either the culturally-tailored All Nations Breath of Life program (ANBL) or Non- tailored (NT). ANBL consists of in-person group sessions and individual telephone calls. We have successfully conducted a pilot study of ANBL and have found very promising results. At 12 months post baseline, all participants will be assessed for smoking status and continuous abstinence. We will randomize 28 groups per site (8 smokers per group) to ANBL or NT for a total sample size of 448 AI/AN smokers. This study is the first controlled trial to examine the efficacy of a culturally-tailored smoking cessation program for AI/ANs. In collaboration with AI/AN colleagues in Oklahoma we designed and successfully piloted the intervention to be culturally-tailored and sustainable in order to enhance its potential for widespread adoption and ultimate impact among AI/AN smokers. If the intervention is successful, the potential health impact is significant because the prevalence of smoking is the highest in this population. PUBLIC HEALTH RELEVANCE: This study is a multi-site trial to test the efficacy of a culturally-tailored smoking cessation program for American Indians. It is the first randomized trial related to smoking cessation to be conducted in this underserved population. The public health impact of this intervention is highly significant because the prevalence of smoking is the highest in American Indians.